[Mechanisms of Cancer Malignancy Elicited by Environmental Chemicals: Analysis Focusing on Cadmium and Bisphenol A].

Humans are continually exposed to various chemicals in the environment. Some of these environmental chemicals not only induce malignant transformation but also enhance the malignant potential of the cancer. In this review, the author summarizes the findings on the effects of environmental chemicals on cancer with a focus on inorganic cadmium (Cd) and organic bisphenol A (BPA). Cd, an established human carcinogen, enhances the invasive capacity of rat liver TRL 1215 cells during malignant transformation by downregulating apolipoprotein E (ApoE), a suppressor of cell invasion, via induction of DNA hypermethylation in its promoter region by the oxidative stress/ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-mediated machinery. BPA, which is recognized as an endocrine disruptor, raises the concern that very high concentrations (beyond environmental levels) of BPA are required for activation of estrogen receptors α/β (ERα/β) in vitro. We identified a BPA metabolite, 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), which exhibited more potent estrogenic activity than BPA. Thus, MBP may be a key candidate for explaining the endocrine-disrupting effects of BPA. In addition, the estrogenic action of MBP can be enhanced by repeated exposure of MCF-7 cells to the actualized ERβ subtype because of the downregulation of ERα in human breast cancer MCF-7 cells. MBP downregulates the expression of the tumor suppressor gene, G protein-coupled estrogen receptor 1 (GPER1), via ERβ signaling.